The long-term goal of this P01 is to understand the intersection of radiation biology and cancer immunology and to translate this research into better therapies with curative potential for patients with cancer. Radiation therapy (RT) can systemically impact the immune system, and recent clinical success of PD1 and CTLA4 immune checkpoint blockade (ICB) has given rise to our overarching hypothesis that the immune stimulatory effects of RT can expand the spectrum of clinical responsiveness when combined with dual ICB across multiple histologies. Our preliminary data and investigative approach bridges studies in both patients and animal models. To achieve our goals, we have developed three Projects, which require close coordination of projects and cores. In Project 1, we will determine the clinical and immunological impact of treating patients on two clinical trials: (i) nivolumab (PD1 mAb) and ipilimumab (CTLA4 mAb) with or without hypofractionated RT (HFRT) in a randomized phase II study in metastatic melanoma; and (ii) and tremelimumab (CTLA4 mAb) and durvalumab (PDL1 mAb) with HFRT at two dose schedules in metastatic pancreatic, lung, and breast carcinoma. In Project 2, we will determine the role of RT in establishing cancer immunity, evaluating the mechanism of anti-viral signaling through pattern recognition receptors and non-coding RNA and examining dendritic cell biology and CD40 activation. In Project 3, we will define the genetic and epigenetic basis of resistance to RT and ICB and examine PDL1 independent pathways to overcome this. Biomarkers revealed in Projects 2 and 3 will be examined using human samples from the clinical trials in Project 1. The Cores for this P01 are essential for our progress including provision of administration support for collaboration (Core A), a state-of-the-art platform for small animal radiation (Core B), and bioinformatics and biostatistical approaches to drive deep learning from data generated in all Projects (Core C). The potential for paradigm shifting impact is to transform the indication of RT from ?local therapy? to key part of a novel ?systemic? immune therapy for meaningful efficacy against metastatic and advanced cancer.